Abstract Mercury (Hg) continues to pose a significant risk to human health reflected by its #3 ranking on the U.S. Agency of Toxic Substances and Disease Registry priority list of hazardous substances, behind only arsenic and lead. Of greatest concern is exposure to the more toxic methylmercury (MeHg) that comes with eating fish. Four billion people world-wide rely on fish as a significant source of dietary protein and essential nutrients. Thus, the ?mercury problem? cannot be solved by simply avoiding the major source of exposure. On the other hand, what constitutes a harmful level of MeHg exposure remains considerably uncertain. For example, federal (US EPA) guidelines for fish consumption are based on a Reference Dose (RfD) value for intake of MeHg, which incorporates 10-fold ?uncertainty factor?. It is known that much of this uncertainty stems from the fact that people metabolize MeHg at widely variable rates and as a result two similarly sized individuals consuming equal amounts of fish could experience as much as a four-fold difference in accumulated MeHg. A solution to this problem lies in developing the knowledge and tools to determine an individual?s predisposition to accumulate MeHg. Yet, several fundamental gaps in the knowledge of how the human body metabolizes and eliminates MeHg remain. Prior research, largely in laboratory animals, supports the notion that microbes in the gut are required for the efficient biotransformation (demethylation) and excretion of toxic MeHg. We have recently obtained substantiating evidence that the rate of MeHg elimination in the human body is reliant on gut microbes. Importantly, we discovered that MeHg elimination rate in a given individual can vary significantly over time and, furthermore, is significantly slowed with exposure to antibiotics. With this evidence, we will test the hypothesis that an individual?s susceptibility for reaching harmful levels of MeHg in the body is regulated by a select number of microbes common to the human gut. We predict these microbes will be present in variable amounts in different individuals, and thus could serve as a biomarker for MeHg metabolism disposition. We also predict a change in abundance of these microbes can be achieved with a probiotic diet supplement. We will test our hypothesis in a coordinated team effort involving experts in MeHg exposure and metabolism in humans, gut microbial ecology in mouse models, and microbial Hg biotransformation and genomics. In three Specific Aims we will: establish gut microbiome samples that exhibit ?fast? and ?slow? MeHg kinetics in humans (Aim1), validate the microbiome?s role in MeHg kinetics using germ free mouse modeling (Aim2) and identify and isolate microbial species responsible for MeHg demethylation in the human gut (Aim3). With knowledge from this study we intend to improve human health practices by: 1) deriving non-invasive tools to identify individuals susceptible to accumulating MeHg and 2) identifying dietary supplement approaches to enhance an individual?s capacity to metabolize and excrete toxic MeHg.